NM_033056.4:c.1917+25_1917+34dupGTGTGTGTGT

Variant names:

• chr10-54132840-T-TACACACACAC
• rs5785040
• NM_033056.4:c.1917+25_1917+34dupGTGTGTGTGT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_033056.4(PCDH15):​c.1917+25_1917+34dupGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000030 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0900
• Publications: 2 publications found

Genes affected

PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

PCDH15 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.1917+25_1917+34dupGTGTGTGTGT		intron_variant	Intron 15 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.1917+25_1917+34dupGTGTGTGTGT		intron_variant	Intron 15 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.1917+34_1917+35insGTGTGTGTGT		intron_variant	Intron 15 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.1917+34_1917+35insGTGTGTGTGT		intron_variant	Intron 15 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150402 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000297 AC: 4 AN: 1345758 Hom.: 0 Cov.: 31 AF XY: 0.00000450 AC XY: 3 AN XY: 666796

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30616

American (AMR) AF: 0.00 AC: 0 AN: 36908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23898

East Asian (EAS) AF: 0.00 AC: 0 AN: 34394

South Asian (SAS) AF: 0.0000257 AC: 2 AN: 77752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5428

European-Non Finnish (NFE) AF: 9.69e-7 AC: 1 AN: 1032352

Other (OTH) AF: 0.0000179 AC: 1 AN: 55878

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0686974), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150402 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 73358

African (AFR) AF: 0.00 AC: 0 AN: 40880

American (AMR) AF: 0.00 AC: 0 AN: 15090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67512

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00 Hom.: 79

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.090

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5785040; hg19: chr10-55892600;